Study on the relation between chorea-acanthocytosis gene and psychiatric disorders

棘细胞舞蹈症是一种常染色体隐性遗传的遗传性神经退行性疾病，在脑病理学中有选择性尾状核和黑质变性的报道。最近，我们发现了编码一种新蛋白Chorein的基因Chac，在日本Chac家族中发现了一个缺失突变。在本研究中，我们克隆了小鼠Chac基因，鉴定了该基因的外显子-内含子结构，并利用基因打靶技术获得了相应于人类疾病突变的引入#60-61外显子缺失的Chac模型小鼠。这些小鼠在变老后开始出现运动障碍和棘细胞增多。在行为学观察中，以移动距离表示的运动活动显著减少，在社会互动测试中，接触时间显著减少。脑病理组织化学观察发现，纹状体区神经元发生凋亡和胶质增生，谷氨酸脱羧酶免疫反应神经元和纤维减少，酪氨酸羟化酶免疫反应纤维减少。在黑质，尤其是在网状部，胶质细胞增多，导致酪氨酸羟基酶免疫反应神经元、谷氨酸脱羧酶免疫反应神经元和纤维以及P物质免疫反应纤维减少。这些发现与其他地方报道的人类结果完全一致。因此，Chac模型小鼠为研究人类疾病提供了一个很好的模型系统。

Chorea-acanthocytosis (CHAC) is a hereditary neurodegenerative disorder with autosomal recessive transmission, in which selective degeneration of caudate nucleus and substantia nigra has been reported in brain pathology. Recently, we have identified the gene, CHAC encoding a novel protein, chorein in which a deletion mutation was found in Japanese CHAC families. In the present study, we have cloned the mouse CHAC cDNA, identified the exon-intron structures of the gene, and then produced a CHAC-model mouse introducing #60-61 exons-deletion corresponding to a human disease mutation by gene-targeting technique. The mice began to show motor disturbance and acanthocytosis after becoming old age. In behavioral observations, locomotor activity expressed as moving distance was significantly decreased, and at social interaction test the contact time was decreased significantly in the model mice. In brain pathology, histochemical observation revealed that neuronal apoptosis and gliosis occurred in the striatum, which lead to the decrease in glutamic acid decarboxylase-immunoreactive neurons and fibers and tyrosine hydroxylase-immunoreactive fibers. In substantia nigra, gliosis was observed especially in the pars reticulata, leading to decrease in tyrosine hydroxylase-immunoreactive neurons, glutamic acid decarboxylase-immunoreactive neurons and fibers and substance P-immunoreactive fibers. These findings are completely consistent with the human results reported elsewhere. The CHAC-model mouse therefore provides a good model system to study the human disease.